Contamination of blood supplies with infectious microorganisms such as HIV, hepatitis and other viruses and bacteria presents a serious health hazard for those who must receive transfusions of whole blood or administration of various blood components such as platelets, red cells, blood plasma, Factor VIII, plasminogen, fibronectin, anti-thrombin III, cryoprecipitate, human plasma protein fraction, albumin, immune serum globulin, prothrombin, plasma growth hormones, and other components isolated from blood. Blood screening procedures which are currently available may miss contaminants. Thus, there is a need for sterilization procedures that effectively neutralize all infectious viruses and other microorganisms but do not damage cellular blood components, do not degrade desired biological activities of proteins, and preferably do not need to be removed prior to administration of the blood product to the patient.
The use of photosensitizers, compounds which absorb light of a defined wavelength and transfer the absorbed energy to an energy acceptor, has been proposed as a solution to the contamination of blood and blood components. Various photosensitizers have been proposed for use as blood additives for pathogen inactivation of blood or blood components. A review of commonly used photosensitizers, and some of the issues of importance in choosing photosensitizers for decontamination of blood products is provided in Goodrich, R. P., et al. (1997), “The Design and Development of Selective, Photoactivated Drugs for Sterilization of Blood Products,” Drugs of the Future 22:159-171.
Some photosensitizers that have been proposed for use for blood component photoirradiation have undesirable properties. For example, European Patent Application 196,515 published Oct. 8, 1986, suggests the use of non-endogenous photosensitizers such as porphyrins, psoralens, acridine, toluidines, flavine (acriflavine hydrochloride), phenothiazine derivatives, and dyes such as neutral red and methylene blue, as blood additives. Another molecule, chlorpromazine, has been used as a photosensitizer; however its usefulness is limited by the fact that it should be removed from any fluid administered to a patient after the decontamination procedure because it has a sedative effect. Protoporphyrin, which occurs naturally within the body, can be metabolized to form a photosensitizer; however, its usefulness is limited in that it degrades the desired biological activities of proteins.
Most preferred with respect to the reduction of pathogens in blood or blood products are endogenous photosensitizers. The term “endogenous” means naturally found in a human or mammalian body, either as a result of synthesis by the body or because of ingestion as an essential foodstuff (e.g. vitamins) or formation of metabolites and/or byproducts in vivo. Examples of such endogenous photosensitizers are alloxazines such as 7,8-dimethyl-10-ribityl isoalloxazine (riboflavin), 7,8,10-trimethylisoalloxazine (lumiflavin), 7,8-dimethylalloxazine (lumichrome), isoalloxazine-adenine dinucleotide (flavine adenine dinucleotide [FAD]), alloxazine mononucleotide (also known as flavine mononucleotide [FMN] and riboflavine-5-phosphate), vitamin Ks, vitamin L, their metabolites and precursors, and napththoquinones, naphthalenes, naphthols and their derivatives having planar molecular conformations. The term “alloxazine” includes isoalloxazines.
The use of the endogenous alloxazine photosensitizers such as those mentioned above to reduce pathogens which may be contained in blood or blood products are disclosed in U.S. Pat. Nos. 6,258,577 and 6,277,337 issued to Goodrich et. al and are herein incorporated by reference in their entirety to the amount not inconsistent.
Endogenously-based derivative photosensitizers useful in this invention include synthetically derived analogs and homologs of endogenous photosensitizers which may have or lack lower (1-5) alkyl or halogen substituents of the photosensitizers from which they are derived, and which preserve the function and substantial non-toxicity thereof. U.S. Pat. No. 6,268,120 to Platz et al. discloses alloxazine derivatives which may also be used to inactivate microorganisms contained in blood or blood components. This patent is also incorporated by reference into the present invention to the amount not inconsistent.
When certain endogenous photosynthesizers are used, certain components which are naturally occurring in blood plasma or in some synthetic blood storage/collection solutions may interact with the photosensitizer during the photoinactivation process and form complexes. The presence of these complexes may increase the rate of side reactions which occur during the photolysis of the photosensitizer. One such complex which may form if 7,8-dimethyl-10-ribityl isoalloxazine (riboflavin) is used as the photosensitizer, is a complex between riboflavin and adenine. Adenine is found in blood plasma as well as being an additive component of some synthetic blood collection/storage solutions.
It is toward this end of preventing damage to blood and blood components to be pathogen reduced by preventing the formation of a photosensitizer-plasma constituent complex (such as adenine) that the present invention is directed.
Several U.S. Patents discuss the removal of plasma and plasma proteins in a pathogen inactivation process using photosensitizers. U.S. Pat. No. 5,360,734 issued Nov. 1, 1994 and U.S. Pat. No. 5,597,722 issued Jan. 28, 1997 both to Chapman et al. discuss treating a blood component containing red blood cells and plasma proteins by removing a portion of the plasma proteins before adding the photoactive agent benzoporphyrin. The treated blood component is prevented from contacting plasma proteins for a period of time (three to eighteen hours) after treatment to prevent binding of the treated cells to IgG proteins in the plasma. These patents do not disclose or suggest the removal of plasma to prevent the formation of specific plasma constituent-photo sensitizer complexes which changes the efficiency of the photosensitizer.